allyl 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-[(1R)-3-hydroxy-1-methyl-2-oxopropyl]-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate -Drug Synthesis Database

【结构式】

【分子编号】30144

【品名】allyl 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-[(1R)-3-hydroxy-1-methyl-2-oxopropyl]-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate

【CA登记号】

【分子式】C₃₆H₃₈NO₈P

【分子量】643.673422

【元素组成】C 67.18% H 5.95% N 2.18% O 19.89% P 4.81%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(XXIX)

Reaction of the acetoxy azetidinone (XIX) with methyl 2-(bromomethyl)butenoate (XX) in the presence of Zn produced adduct (XXI). Reduction of the ester group of (XXI) with DIBAL-H, followed by protection of the resulting allyl alcohol with trityl chloride gave (XXII). Further ozonolysis of (XXII) generated ketone (XXIII). Condensation of (XXIII) with allyl glyoxylate (XXIV) gave hemiaminal (XXV). After treatment of (XXV) with SOCl2, reaction with triphenylphosphine produced phosphorane (XXVI). Acid deprotection of the trityl and silyl groups of (XXVI), followed by acetylation with AcCl gave acetate ester (XXVII). The secondary hydroxyl group of (XXVII) was then protected with allyl chloroformate to afford carbonate (XXVIII). Then, deprotection of the acetate ester of (XXVIII) with methanolic NaOMe gave hydroxy ketone (XXIX). Finally, cyclization between keto and phosphorane groups of (XXIX) in boiling toluene furnished the carbapenem compound (XXX).

参考文献中间体

合成目标

【1】 Dininno, F.P.; Dykstra, K.D.; Wildonger, K.J.; Blizzard, T.A.; Wilkening, R.R.; Hammond, M.L.; Ratcliffe, R.W.; Cama, L.D.; Synthesis and in vitro evaluation of 1beta-methyl-2-(sulfonamido) methyl-carbapenems: Discovery of a novel PBP2a-binding, anti-MRSA 1,8-naphthosultamyl pharmacophore. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-33.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIX)	11687	(2R,3R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetanyl acetate	C₁₃H₂₅NO₄Si	详情	详情
(XX)	30136	methyl (Z)-2-(bromomethyl)-2-butenoate	C₆H₉BrO₂	详情	详情
(XXI)	30164	methyl 2-[(1S)-1-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-oxoazetidinyl]ethyl]acrylate	C₁₇H₃₁NO₄Si	详情	详情
(XXII)	30137	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1S)-1-methyl-2-[(trityloxy)methyl]-2-propenyl]-2-azetidinone	C₃₅H₄₅NO₃Si	详情	详情
(XXIII)	30138	(3S,4R)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-4-[(1R)-1-methyl-2-oxo-3-(trityloxy)propyl]-2-azetidinone	C₃₄H₄₃NO₄Si	详情	详情
(XXIV)	30139	allyl 2-oxoacetate	C₅H₆O₃	详情	详情
(XXV)	30140	allyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R)-1-methyl-2-oxo-3-(trityloxy)propyl]-4-oxoazetidinyl]-2-hydroxyacetate	C₃₉H₄₉NO₇Si	详情	详情
(XXVI)	30141	allyl 2-[(2R,3S)-3-((1R)-1-[[tert-butyl(dimethyl)silyl]oxy]ethyl)-2-[(1R)-1-methyl-2-oxo-3-(trityloxy)propyl]-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate	C₅₇H₆₂NO₆PSi	详情	详情
(XXVII)	30142	allyl 2-[(2R,3S)-2-[(1R)-3-(acetoxy)-1-methyl-2-oxopropyl]-3-[(1R)-1-hydroxyethyl]-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate	C₃₄H₃₆NO₇P	详情	详情
(XXVIII)	30143	allyl 2-[(2R,3S)-2-[(1R)-3-(acetoxy)-1-methyl-2-oxopropyl]-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate	C₃₈H₄₀NO₉P	详情	详情
(XXIX)	30144	allyl 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-[(1R)-3-hydroxy-1-methyl-2-oxopropyl]-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate	C₃₆H₃₈NO₈P	详情	详情
(XXX)	23834	allyl (4S,5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-(hydroxymethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₁₈H₂₃NO₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXIX)

Condensation of azetidinone (XXIX) with sultam (VIIIb) to afford (LI), which was cyclized to the corresponding carbapenem (LII) upon refluxing in toluene. The title compound was then prepared by a sequence analogous to Scheme 25884901g.

参考文献中间体

合成目标

【1】 Wilkening, R.R.; Wildonger, K.J.; Ratcliffe, R.W.; et al.; Synthesis and evaluation of anti-MRSA 1beta-methyl-2-(naphthosultamyl) methyl-carbapenems: Discovery of L-786,392. 38th Intersci Conf Antimicrob Agents Chemother (Sept 24 1998, San Diego) 1998, Abst F-32.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VIIIb)	30125	6-[2-[(triethylsilyl)oxy]ethyl]-2H-naphtho[1,8-cd]isothiazole-1,1(2H)-dione	C₁₈H₂₅NO₃SSi	详情	详情
(XXIX)	30144	allyl 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-[(1R)-3-hydroxy-1-methyl-2-oxopropyl]-4-oxoazetidinyl]-2-(triphenylphosphoranylidene)acetate	C₃₆H₃₈NO₈P	详情	详情
(LI)	30162	allyl 2-((2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-[(1R)-3-[1,1-dioxo-6-[2-[(triethylsilyl)oxy]ethyl]-2H-naphtho[1,8-cd]isothiazol-2(1H)-yl]-1-methyl-2-oxopropyl]-4-oxoazetidinyl)-2-(triphenylphosphoranylidene)acetate	C₅₄H₆₁N₂O₁₀PSSi	详情	详情
(LII)	30163	allyl (4S,5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-[[1,1-dioxo-6-[2-[(triethylsilyl)oxy]ethyl]-2H-naphtho[1,8-cd]isothiazol-2(1H)-yl]methyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate	C₃₆H₄₆N₂O₉SSi	详情	详情

Extended Information